Sequential Insertion of Alkynes, Alkenes, and CO into the Pd–C Bond of ortho-Palladated Primary Phenethylamines: from η3-Allyl Complexes and Enlarged Palladacycles to Functionalized Arylalkylamines

The eight-membered metallacycles arising from the insertion of 1 equiv of alkyne into the Pd–C bond of ortho-metalated homoveratrylamine and phentermine can further react with alkenes to give two different types of mononuclear complexes depending on the nature of the olefin. When terminal alkenes (styrene and ethyl acrylate) are used, a mixture of the anti/syn η3-allyl Pd(II) complexes are isolated, which evolve slowly to the syn isomers by heating the mixtures appropriately. These η3-allyl Pd(II) complexes do not react with CO or weak bases, but when they are treated with a strong base, such as KOtBu, they afford Pd(0) and the functionalized starting phenethylamines containing a 1,3-butadienyl substituent in an ortho position. When 2-norbornene was used instead of terminal alkenes, the strained olefin inserts into the alkenyl Pd(II) complex to afford a 10-membered norbornyl palladium(II) complex, in which the new C,N-chelate ligand is coordinated to the metal through an additional double bond, occupying three coordination positions. The reactivity of these norbornyl complexes depends on the substituents on the inserted alkenyl fragment, and thus they can further react with (1) KOtBu, to give Pd(0) and a tetrahydroisoquinoline nucleus containing a tricyclo[3.2.1]octyl ring, or (2) CO and TlOTf, to afford Pd(0) and amino acid derivatives or the corresponding lactones arising from an intramolecular Michael addition of the CO2H group to the α,β-unsaturated ester moiety. Crystal structures of every type of compound have been determined by X-ray diffraction studies.


■ INTRODUCTION
Palladium is one of the most versatile transition metals in organic synthesis, given its well-known ability to catalyze the formation of C−C and C−heteroatom bonds. 1,2 Nevertheless, the extraordinarily high variability of applications of palladium relies just on a few elementary steps inherent to its reactivity, and among them, the migratory insertion reaction of an unsaturated ligand into a Pd−C bond stands out. 3−5 Thus, a myriad of methods to functionalize alkenes, 3,6 alkynes, 7 or allenes 8 through Pd catalysis have been reported so far.
Multicomponent reactions, where several reagents assemble sequentially giving rise to complex structures, are valuable protocols, since they represent an effective modular approach to green organic synthesis. 9 Nevertheless, transition-metalcatalyzed processes involving the use of several unsaturated coupling partners in the reaction mixture are challenging fields due to the difficulty in controlling the order of reactivity: that is, the control of regioselectivity of the migratory insertion sequence for the different unsaturated reagents. 10−12 Some successful examples of these types of reactions are the copolymerization of alkenes and CO (Scheme 1a) 13 and the copolymerization of olefins with and without polar groups, 14 among others. 15−17 Moreover, impressive progress has been made on intramolecular cascade reactions where different unsaturated moieties are involved (Scheme 1b). 5,18 In the latter case, however, the selectivity is usually determined by the structure of the substrate itself.
While catalytic conditions make difficult the aforementioned control of the selectivity, stoichiometric reactions can offer the advantage of stepwise insertion paths for the synthesis of valuable organic products. 19−23 Our research group has previously reported the functionalization of primary phenethylamines through the isolation of ortho-palladated intermediates. 24−26 These types of arylalkylamines constitute the core of many relevant biomolecules, such as neurotransmitters (i.e., dopamine), amino acids (i.e., phenylalanine), or marketed psychoactive drugs. The catalytic functionalization of these scaffolds has proven challenging, due to the strong coordination ability of the primary amine group to Pd(II). 27 Hence, the study of the stoichiometric functionalization of primary phenethylamines can provide alternative routes to modify these interesting molecules. For instance, the sequential insertion of alkynes and CO or of alkynes and isocyanides into ortho-palladated derivatives allowed us to synthesize medium-sized rings such as eightmembered benzazocinones (Scheme 2). 20,21 We have previously reported the synthesis and isolation of stable eight-membered C,N-palladacycles arising from the insertion of one molecule of alkyne into the Pd−C bond of ortho-palladated phentermine and homoveratrylamine (Chart 1). 20 We present here the results of a study on the insertion of alkenes and alkenes/CO into these eight-membered alkenyl palladacycles. We have studied the new organometallic species generated upon each insertion, as well as the final functionalized organic products, formed through depalladation of the final organopalladium compounds. The overall processes rendering the final organopalladium complexes involve the sequential insertion of (a) alkynes and alkenes or (b) alkynes, alkenes, and CO into the Pd−C bond of the ortho-metalated derivatives from the primary phenethylamines.
syn-1a or anti-/syn-2a in CH 2 Cl 2 . The ratio between isomers, for both 1a and 2a, practically did not change after 48 h in CDCl 3 solution at room temperature (by 1 H NMR). However, the conversion to the syn isomers was complete after heating CDCl 3 solutions of the mixtures at 60°C for 10 days (syn-1a) or 48 h (syn-2a; by 1 H NMR; Figure 1 and Table 1).
Since anti-1 and anti-2 complexes practically did not isomerize to the syn-1 and syn-2 derivatives at room temperature (Table 1), both isomers should be formed during the reaction. We proposed that the formation of anti-/syn-1 or anti-/syn-2 could be envisioned by the mechanism depicted in Scheme 4. Insertion of one molecule of the alkene into the Pd−C bond of the starting palladacycle (a or b) would afford the 10-membered alkyl palladacycle I. For this intermediate,  we propose that the R′ group is at the carbon atom bonded to Pd(II), because (1) this is the regiochemistry that explains the formation of the allyl moiety coordinated to Pd(II) in complexes 1a,b and 2a,b and (2) this is the most frequent regioisomer found in the insertion of electron-poor alkenes into the Pd−C bonds of neutral complexes. 22,28 Intermediate I could undergo β-hydride elimination to give the cisoid-(diene)PdH species II. Syn addition of Pd−H to the alkene moiety with regioselectivity in contrast with its previous elimination results in the formation of the η 3 -allyl complex anti-1 or anti-2 (Scheme 4), which seems to be formed preferentially as the kinetic product. On the other hand, the transoid-(diene)PdH intermediate III could be generated from II upon decoordination and rotation of the tertiary olefin moiety, prior to the Pd−H addition step, hence giving rise to the formation of the syn isomer. The thermal isomerization of the complexes anti-1 and anti-2 to the syn isomers at 60°C (Table 1) proceeded by the usual η 3 −η 1 −η 3 rearrangement. Complexes 1 and 2 were fully characterized by elemental analyses and NMR and IR spectroscopic techniques. The 1 H NMR spectra of all the allyl complexes showed the diastereotopic nature of the hydrogen atoms of the NH 2 and CH 2 groups, as well as both of Me groups of the CMe 2 moiety for 1b and 2b. The most characteristic signal was that corresponding to the methine group of the inserted fragment, which appeared as a doublet of doublets in the range 4.85− 5.16 ppm for the anti isomers and 4.75−4.84 ppm for the syn isomers. The two coupling constants 3 J HH (anti, 11.2 ≤ 3 J HH ≤ 12.3 Hz, average value 11.7 Hz; syn, 9.6 ≤ 3 J HH ≤ 11.0 Hz, average value 10.3 Hz; anti, 4.5 ≤ 3 J HH ≤ 5.2 Hz, average value 4.7 Hz; syn, 3.7 ≤ 3 J HH ≤ 4.2 Hz, average value 4.0 Hz) were slightly smaller for the syn isomers than for the anti isomers.
Some catalytic transformations involving the sequential migratory insertion of alkynes and alkenes into a Pd− C 11,12,17,29 or a Pd−H 15 bond have been reported in the literature. In these processes, substituted 1,3-butadienes are formed. The mechanism proposed for those catalytic transformations does not consider the formation of η 3 -allyl intermediates. In our case, however, the presence of a coordinating group, such as NH 2 , may favor the isomerization of the 1,3-butadiene to form a stabilized allyl Pd(II) complex. As far as we are aware, this is the first stoichiometric study where the sequential migratory insertion of an alkyne and an alkene has been studied.
Reactivity of the η 3 -Allyl Complexes. The nucleophilic attack to η 3 -allyl Pd(II) intermediates to give functionalized alkenes is a well-known strategy in organic synthesis. 30 However, most of the times the key η 3 -allyl Pd(II) species are generated through the oxidative addition of allyl halides, pseudohalides or acetates to Pd(0). We wondered if the η 3 -allyl complexes 1 and 2 could undergo the attack of a suitable nucleophile to render an organic derivative. Hence, we performed a range of reactions with several nucleophiles, such as KCN, [Tl(acac)], p-toluidine, and the phosphorus ylide Ph 3 PCHCOMe. There was no reaction at room temperature with any of these nucleophiles. When the reaction mixture was heated in refluxing toluene, complicated mixtures were produced. The reaction of complex 1b and dimethyl malonate in the presence of Cs 2 CO 3 (CHCl 3 , room temperature) afforded an anti/syn mixture of isomers of a new complex containing the η 3 -allyl moiety and a coordinated  Organometallics pubs.acs.org/Organometallics Article malonate, whose structures were not studied further. When a solution of this complex in CHCl 3 was heated at 60°C, again a complicated mixture was obtained. In order to facilitate the nucleophilic attack, we performed the reaction of the η 3 -allyl complex 1b with p-toluidine in the presence of TlOTf, which would generate a cationic complex by replacing the Cl − ligand by OTf − in the coordination sphere of Pd(II). In this case, the stable cationic η 3 -allyl complex 3b was isolated, which contained a coordinated p-toluidine ligand (Scheme 5). This complex was stable in refluxing toluene and did not decompose to the expected organic product.
The 1 H NMR of complex 3b at room temperature showed some broad signals and seemed to correspond to a mixture of two isomers with a fluxional behavior ( Figure 4). Perhaps the most significant resonances are those attributed to the Me groups: three sharp singlets at 1.45 (3 H), 1.42 (3 H), and 1.26 ppm (2.2 H) and two broad singlets at 2.28 (5.4 H) and 0.94 ppm (2.2 H). When the spectrum was measured at −40°C, the broad singlet below 1 ppm become sharper, and the signal at 2.28 ppm split into two new singlets with the relative intensities 3:2.2. According to these data, we assumed that both isomers, anti-/syn-3b, are formed in a 1.33/1 ratio, one of which presented a fluxional behavior in solution. The less stable isomer should be anti-3b due to steric hindrance of the toluidine ligand and the substituent on the terminal allylic carbon, and for it, it was reasonable to suppose that the neutral ligand could be coming in and out of the metal coordination sphere.
The crystal structure of the η 3 -allyl complex syn-3b·CH 2 Cl 2 was determined by X-ray diffraction ( Figure 5), showing that the phenyl and benzyl substituents at the meso and terminal carbon atoms of the allylic unit occupied mutually syn positions and indicating that this was, in fact, the most stable isomer. For this complex there were two independent molecules in the asymmetric unit (A and A′). For molecule A, the palladium atom exhibited a square-planar geometry (mean deviation from the plane: X−Pd(1)−N(1)−N(2) 0.0067 Å, where X = centroid from C(7), C(8), and C(9) atoms). Both amino groups were coordinated in cis positions. The other two coordination sites were occupied by the allyl moiety, which was η 3 -bonded via C(7), C(8), and C(9), with a C(7)−C(8)−C(9) angle of 116.9(2)°. The allyl plane, defined by atoms C(7), C(8), and C(9), formed a dihedral angle of 118.1°with the Pd(II) coordination plane. The aromatic rings formed angles of 71.3°(metalated ring), 65.5°(phenyl ring at C7), 71.9°(phenyl ring at C8), 73.3°(phenyl ring at C14), and 92.4°(toluidine ring) with respect to the Pd coordination plane, to avoid steric hindrance. Hydrogen bond interactions were observed between the cationic palladium moiety and the OTf − anion (see the Supporting Information).   Organometallics pubs.acs.org/Organometallics Article Additionally, we studied the behavior of the anti-/syn-1a,b complexes toward a strong base. The reaction of these complexes with KO t Bu in toluene under a N 2 atmosphere afforded Pd(0) and the functionalized phenethylamines containing a 1,3-butadienyl substituent in an ortho position (4a,b; Scheme 6). We did not observe intramolecular cyclization arising from the possible nucleophilic attack of the NH 2 group to the η 3 -allyl moiety. The compound 4a was a colorless solid and was easily isolated, but 4b was obtained as a liquid. In order to get a more easily isolable derivative, triflic acid was added to a solution of compound 4b in diethyl ether (Scheme 6). The corresponding ammonium triflate 5b precipitated in the reaction mixture and was obtained as a white powder in moderate yield (50%).
Miura et al. 12 described the intermolecular three-component coupling of aryl iodides, diarylacetylenes, and alkenes in the presence of palladium acetylacetonate and silver acetate as catalysts, to give the corresponding 1:1:1 and 1:2:1 coupling products (1,3-butadiene and 1,3,5-hexatriene derivatives, respectively). The mechanism proposed for these catalytic transformations followed the sequential steps analogous to those of the synthesis of compounds 4 reported here, (1) formation of an aryl Pd(II) complex (either by oxidative addition or C−H activation), (2) alkyne insertion into the Pd−C bond to form an alkenyl complex, (3) alkene insertion into the Pd−C bond to form an alkyl intermediate, and (4) β-H elimination, assisted by a base, to afford the final diene. In our case, and due to the particular nature of the initial aryl group, we have been able to isolate all of the organometallic intermediates involved in the process.
We also attempted to insert a third unsaturated molecule into the Pd−C bonds of the η 3 -allyl complexes by bubbling CO through a solution of 1b in CH 2 Cl 2 (room temperature, 4 h). Nevertheless, no reaction was observed, probably because these complexes were too stable. A similar reaction, with addition of TlOTf and use of THF as the solvent, led to a cationic complex with no CO inserted.
Insertion of 2-Norbornene into the Pd−C Bond. Synthesis and Structure of 10-Membered Norbornyl Palladium(II) Complexes. In contrast to styrene or ethyl acrylate, when 1 equiv of 2-norbornene was added to a solution of the alkenyl complex b (arising from insertion of one molecule of diphenylacetylene into the Pd−C bond of palladacycle B; see Scheme 7 for its structural formula), no insertion reaction was observed, neither at room temperature nor on heating the mixture to 65°C in CHCl 3 . We also attempted the insertion reactions using as starting materials the eight-membered palladacycles c and d, arising from the Organometallics pubs.acs.org/Organometallics Article insertion of methyl phenylpropiolate and 1-phenyl-1-propyne, respectively, into the Pd−C bond of complex B. When palladacycle d was used, the reaction at room temperature led to a new species that was tentatively assigned to the norbornene coordination monomer species 6d (Scheme 7), which could not be fully characterized, since it evolved easily to the starting dimeric complex d when we tried to crystallize it. Nevertheless, when these reaction mixtures (palladacycle c or d and 2-norbornene) were heated to 65°C, we could successfully isolate the complexes 7c,d, where the insertion of the 2-norbornene moiety into the alkenyl Pd(II) complex had taken place (Scheme 7). These complexes have a monomeric nature, since the Pd center completes its coordination sphere with the intramolecular olefin moiety. The crystal structures of complexes 7c·CHCl 3 and 7d·1/ 2CHCl 3 were solved by X-ray diffraction studies (see Figure 7 and the Supporting Information), and both showed similar features. For the complex 7c·CHCl 3 , the atoms Cl(1), N(1), and C(1) together with the midpoint of the C(3)−C(4) double bond form a square plane around the palladium atom (mean deviation from the plane: Pd(1)−C(1)−N(1)−Cl(1)− X 0.0230 Å, where X = centroid from C(3) and C(4) atoms). The norbornene unit adopted an exo conformation, arising from the syn addition of the Pd−C bond to the exo face of the olefin, as expected. The C(3)−C(4) double bond forms an angle of 61.8°with the palladium coordination plane. The methyl and phenyl substituents are mutually trans, which requires the isomerization of the first inserted alkyne. This arrangement reduces the steric hindrance between the substituents and is the normal behavior for di-inserted derivatives containing cyclometalated amines. 31 We performed an analogous experiment reversing the order of the addition of the unsaturated reagents. That is, we studied the reactivity of the previously reported norbornyl derivative e (arising from the insertion of 2-norbornene into the sixmembered palladacyle B) toward alkynes (Scheme 8). A suspension of the norbornyl Pd(II) complex e in CHCl 3 was The complex 7d, which arose from a reverse insertion order of the reagent addition, was isolated in 20% yield from the reaction mixture. In this reaction, palladacycle b was also formed. The formation of 7d could be explained through the deinsertion of the 2-norbornene fragment in e to give the starting palladacycle B, which in turn would undergo the sequential insertion of the alkyne and 2-norbornene. The ability of this cyclic olefin to insert reversibly into Pd−aryl bonds is well-known. This behavior has promoted the use of norbornene as an essential ligand in the functionalization of haloarenes: for instance, in the versatile Catellani type reaction. 2 We tried to apply this strategy to obtain the diphenylacetylene/2-norbornene insertion derivative. Nevertheless, the reaction of the norbornyl complex e with diphenylacetylene gave rise mainly to the stable eightmembered palladacycle b, arising from monoinsertion of the alkyne (Scheme 8). That is, the olefin did not insert into the Pd−C bond of b, as noted above. The synthesis of alkenyl palladacycles arising from the insertion of one molecule of alkyne into the Pd−C bond of a starting complex is not always a simple task, due to the possibility of di-and tri-insertion processes. This aspect is especially relevant when a very electrophilic alkyne, such as dimethyl acetylenedicarboxylate (DMAD), is used. We have previously tried to isolate the palladacycle f arising from monoinsertion of DMAD into the Pd−C bond of B; nevertheless, mixtures of mono-, di-, and tri-inserted products were obtained (Scheme 9). We thought that performing the reaction of B and DMAD in the presence of 2-norbornene could drive the reaction to the formation of a sequential DMAD/norbornene insertion product, given the fact that norbornene seems to react readily with other monoinserted alkyne derivatives. Indeed, when a solution of the palladacycle B in CHCl 3 was heated to 65°C in the presence of 1 equiv of DMAD and 1 equiv of 2-norbornene, the alkyne/alkene sequential insertion product 7f was isolated in good yield (Scheme 9). The crystal structure of complex 7f was also solved by X-ray diffraction studies (see the Supporting Information) and showed features similar to those discussed for 7c·CHCl 3 .
Reactivity of the Norbornyl Complexes. We explored the reactivity of the complex 7f toward KO t Bu in MeCN at 78°C. From the reaction mixture, we could isolate the tetrahydroisoquinoline derivative 8f by treatment of the crude product with HOTf: that is, from the protonation of V (Scheme 10). A possible path to explain the formation of 8f would involve the intramolecular carbopalladation of the alkene moiety, giving rise to a cyclopropyl ring. The new organometallic intermediate IV would then undergo a C−N coupling process with reductive elimination of Pd(0). Several Pd-catalyzed procedures to promote the cyclopropanation of 2-norbornene have been reported in the literature. 32 Some of these procedures rely on the migratory insertion of norbornene into a Pd alkynyl 33 or Pd alkenyl 34 complex, and some organometallic intermediates similar to complexes 7 have been proposed, where the alkenyl moiety is coordinated intramolecularly to Pd.
The crystal structure of 8f was solved by X-ray diffraction studies ( Figure 8) and showed the isoquinoline nucleus derived from phentermine substituted at C1 with a methoxycarbonyl group and a tricyclo[3.2.1]octyl ring. It is worth noting that highly strained hydrocarbons such as this cyclopropane-containing norbornyl moiety have been tested as new highly energetic materials for liquid-fueled propulsion systems. 35 We studied whether a further insertion of an unsaturated molecule could be carried out in the complexes 7c,d,f, obtained after alkyne/norbornene insertion. Complex 7f did not react when it was stirred in CHCl 3 in the presence of CO at room temperature for 5 h. When the reaction mixture was heated to 65°C, a complicated mixture was formed. In order to facilitate the insertion of CO, we performed the reaction in the presence of TlOTf in acetone, hence generating a cationic Pd(II) intermediate in situ. In this case, the reaction afforded When the cationic derivatives of complexes 7c,d (generated in situ) reacted with CO at room temperature, the amino acid derivatives 10c,d were obtained (Scheme 11). In the case of 10d, intramolecular cyclization to give 9d took place after heating at 65°C in CHCl 3 for 7 days. As expected, the derivative 10c was stable upon heating, since it was not activated for the Michael addition step, as occurred in the cases of the alkenyl complexes bearing a CO 2 Me substituent.
The crystal structure of 9f·Et 2 O has been solved by X-ray diffraction studies ( Figure 9) and showed an ammonium salt derived from the starting phentermine containing a bicyclo[2.2.1]heptane lactone substituent. The hexahydro-4,7-methanoisobenzofuran-1(3H)-one core is a known compound that has attracted interest because of its potential use as a prostaglandin/thromboxane receptor antagonist. 36 The most frequent routes for its synthesis involved (a) the cycloaddition reaction of furan-2(5H)-one and cyclopentadiene 37 and (b) the oxidation of cis-2,3-bis(hydroxymethyl)bicyclo[2.2.1]heptane, which could be performed in a stoichiometric way with standard organic oxidants 38 or by catalysis, with the use of enzymes 39 or transition metals. 40 The crystal structure of 10c has also been determined by Xray diffraction studies (Figure 10), and it showed the ammonium salt derived from the sequential insertion of alkyne/norbornene/CO into the initial phentermine palladacycle. Both substituents (the carboxylate and the alkenyl groups) at the norbornadienyl moiety were in an exo disposition. Organometallics pubs.acs.org/Organometallics Article

■ CONCLUSION
In summary, the stoichiometric sequential insertion of alkynes and alkenes into the Pd−C bond of metalated phenethylamines has been studied. The result of these reactions depends on the nature of the olefin used. The insertion of styrene or ethyl acrylate into the eight-membered palladacycle arising from monoinsertion of diphenylacetylene affords the η 3 -allyl species 1 or 2, via sequential β-H elimination/hydropalladation steps. However, the insertion of 2-norbornene leads to norbornyl Pd(II) complexes with an alkenyl moiety intramolecularly coordinated to the metal center. The treatment with a strong base of the organometallic complexes obtained upon the sequential insertion of alkyne/ alkene (1, 2, and 7) also led to different results. While the η 3allyl complexes 1 and 2 afforded 1,3-butadienyl-substituted phenethylamines (4b and 5b), the norbornyl Pd derivative 7f gave a tetrahydroisoquinoline derivative upon cyclopropanation of the norbornene fragment and C−N coupling (8f).
The η 3 -allyl complexes 1 and 2 were unreactive toward CO insertion. In contrast, the norbornyl derivatives 7c,d,f afforded interesting amino acid or lactone derivatives upon CO insertion into the Pd−C bond and subsequent hydrolysis, under the appropriate conditions.
Overall, we have shown that the isolation of the organometallic intermediates obtained upon stepwise insertion of alkynes and alkenes into palladated phenethylamines allows the synthesis of functionalized primary phenethylamines. These stoichiometric routes avoid the problems associated with substrates that make difficult the development of catalytic processes (such as primary alkylamines) and allow the control of the regioselective insertion of the different unsaturated coupling partners.

■ EXPERIMENTAL SECTION
Caution! Special precautions should be taken in handling thallium(I) compounds, which are toxic.
General Procedures. Infrared spectra were recorded on a PerkinElmer 16F-PC-FT spectrometer. C, H, N, and S analyses were carried out with a LECO CHNS-932 microanalyzer. Conductance measurements and melting point determinations were carried out as described elsewhere. 41 Unless stated otherwise, NMR spectra were recorded in CDCl 3 with Bruker Avance 300, 400, and 600 spectrometers. Chemical shifts are referenced to TMS ( 1 H and 13 C{ 1 H}). Signals in the 1 H and 13 C NMR spectra of all compounds were assigned with the help of APT, HMQC, and HMBC experiments. High-resolution electrospray ionization mass spectra (ESI-MS) were recorded on an Agilent 6220 Accurate-Mass time-offlight (TOF) LC/MS. Reactions were carried out at room temperature without special precautions against moisture unless specified otherwise. The groups C 6 H 4 and C 6 H 2 are denoted by Ar.  19 were prepared as previously reported. TlOTf was prepared by the reaction of Tl 2 CO 3 and HO 3 SCF 3 (1/2) in water and recrystallized from acetone/Et 2 O. Chart 2 gives the numbering schemes for the new organometallic and organic derivatives.
Synthesis of anti-/syn-1a. Styrene (23 μL, 0.202 mmol) was added to a solution of palladacycle a (110 mg, 0.100 mmol) in CH 2 Cl 2 (10 mL), and the mixture was stirred for 20 h. The resulting    Synthesis of anti-/syn-1b. Method A. Styrene (52 μL, 0.453 mmol) was added to a solution of palladacycle b (200 mg, 0.213 mmol) in CH 2 Cl 2 (10 mL). The solution was stirred for 12 h, the solvent was concentrated to ca. 5 mL, Et 2 O (5 mL) was added, and the resulting suspension was filtered through a plug of Celite. The filtrate was concentrated to ca. 1 mL, and n-pentane (20 mL) was added. The suspension was filtered, and the pale yellow solid was washed with n-pentane (2 × 5 mL) and air-dried to give a mixture of anti-/syn-1b (ratio ca. Method B. In a different preparation, it was possible to obtain two different crops by fractional crystallization, each of them enriched in one of the isomers. Styrene (30 μL, 0.262 mmol) was added to a solution of palladacycle b (120 mg, 0.128 mmol) in CH 2 Cl 2 (10 mL). The mixture was stirred for 12 h and filtered through a plug of Celite. The filtrate was concentrated to ca. 3 mL, and Et 2 O (15 mL) was added. The resulting suspension was filtered, and the solid was airdried to afford 57 mg of an anti-enriched mixture of both isomers (anti/syn = 3/1). The mother liquors were concentrated to ca. 3 mL, and n-pentane (20 mL) was added. The resulting suspension was filtered, and the solid was air-dried to afford 25 mg of a syn-enriched mixture of both isomers (anti/syn = 1/3). Almost spectroscopically pure samples of anti-and syn-1b could be obtained by growing single crystals from the enriched mixtures. Data for anti-1b are as follows. 1   anti/syn Isomerization of 1b. An NMR tube was charged with a 2.5/1 mixture of anti-/syn-1b (20 mg) and CDCl 3 (0.6 mL), and the solution was heated at 60°C. The sample was checked by 1 H NMR periodically, until no change was observed. After 5 days at 60°C, a 1/ 10 mixture of anti-/syn-1b was obtained.
Synthesis of anti-/syn-2a. Ethyl acrylate (40 μL, 0.367 mmol) was added to a solution of palladacycle a (200 mg, 0.183 mmol) in CH 2 Cl 2 (10 mL), and the mixture was stirred for 48 h. The resulting mixture was filtered through a plug of Celite, the filtrate was concentrated to ca. 1 mL, and Et 2 O (20 mL) was added. The suspension was filtered, and the pale yellow solid was washed with Et 2 O (2 × 5 mL) and air-dried to give an anti-/syn-2a mixture (171 mg; ratio ca. 5/1 by 1 H NMR). The filtrate was concentrated to ca. 1 mL, and n-pentane (20 mL) was added. The resulting suspension was filtered, and the solid was air-dried to afford a anti-/syn-2a mixture (30 mg; ratio ca.  anti/syn Isomerization of 2a. An NMR tube was charged with a 5/1 anti-/syn-2a mixture (20 mg) and CDCl 3 (0.6 mL), and the solution was heated at 60°C. The sample was checked by 1 , 1 H, H3), 6.87−6.91 (m, partially obscured by the resonance of H6, 2 H, Ph), 6.93 (s, 1 H, H6) Synthesis of anti-/syn-2b. Method A. Ethyl acrylate (50 μL, 0.460 mmol) was added to a solution of palladacycle b (200 mg, 0.213 mmol) in CH 2 Cl 2 (10 mL). The solution was stirred for 12 h and then concentrated to ca. 5 mL. Et 2 O (5 mL) was added, and the resulting suspension was filtered through a plug of Celite. The filtrate was concentrated to ca. 1 mL, and n-pentane (20 mL) was added. The suspension was filtered, and the pale yellow solid was washed with npentane (2 × 5 mL) and air-dried to give as anti-/syn-mixture (ratio ca. Method B. In a different preparation, it was possible to obtain two different crops by fractional crystallization, each of them enriched in one of the isomers. Ethyl acrylate (40 μL, 0.262 mmol) was added to a solution of palladacycle b (150 mg, 0.160 mmol) in CH 2 Cl 2 (10 mL). The mixture was stirred for 12 h and then filtered through a plug of Celite. The filtrate was concentrated to ca. 2 mL, and Et 2 O (15 mL) was added. The resulting suspension was filtered, and the solid was washed with Et 2 O (2 × 5 mL) and air-dried to afford 58 mg of a syn-enriched mixture of both isomers (anti/syn = 1/3). The mother liquors were concentrated to ca. 5 mL and cooled to 0°C. A suspension formed, which was filtered, and the solid was air-dried to afford 60 mg of an anti-enriched mixture of both isomers (anti/syn = 3/1). Almost spectroscopically pure samples of anti-and syn-2b could be obtained by growing single crystals from the enriched mixtures. Data for anti-2b are as follows. 1    anti/syn Isomerization of 2b. An NMR tube was charged with a 1.25/1 anti-/syn-1b mixture (20 mg) and CDCl 3 (0.6 mL), and the solution was heated at 60°C. The sample was checked by 1 H NMR periodically, until no change was observed. After 48 days at 60°C, a 1/20 anti-/syn-2b mixture was obtained.
Synthesis of anti-/syn-3b. TlOTf (56 mg, 0.158 mmol) was added to a suspension of complex 1b (90 mg, 0.157 mmol) in acetone (10 mL), and the resulting mixture was stirred for 2 h. The solvent was removed, and CH 2 Cl 2 (15 mL) was added. The suspension was filtered through a plug of Celite, p-toluidine (17 mg, 0.159 mmol) was added to the filtrate, and the mixture was stirred for another 30 min. The solvent was concentrated to ca. 1 mL, and n-pentane was added. The suspension was filtered, and the pale yellow solid was washed with cold n-pentane (2 × 5 mL) and air-dried to give an anti-/syn-3b mixture (ratio ca. in dry toluene (10 mL), under a nitrogen atmosphere. The mixture was heated at 100°C for 12 h. Decomposition to metallic palladium was observed. The solvent was removed, and CH 2 Cl 2 (20 mL) was added to the residue. The resulting suspension was filtered through a plug of Celite, the filtrate was concentrated to ca. 1 mL, n-pentane (20 mL) was added, and the mixture was cooled to 0°C. The resulting suspension was filtered, and the solid was air-dried to give 4a·1/2H 2  Synthesis of 5b·H 2 O. In a Carius tube, KO t Bu (250 mg, 2.04 mmol) was added to a solution of anti-/syn-1b (120 mg, 0.209 mmol) in dry toluene (10 mL), under a nitrogen atmosphere. The mixture was heated at 100°C for 12 h. Decomposition to metallic palladium was observed. The solvent was removed, and Et 2 O (20 mL) was added to the residue. The suspension was filtered through a plug of Celite, and the solvent was removed from the filtrate to give crude 4b as an oily residue, which was was characterized by 1 H NMR. Data for 4b are as follows. 1  Synthesis of [Pd{C,N-C(Ph)C(CO 2 Me)C 6 H 4 CH 2 CMe 2 NH 2 -2}-Cl(C 7 H 10 )] (6d). 2-Norbornene (C 7 H 10 ; 25 mg, 0.265 mmol) was added to a solution of palladacycle d (65 mg, 0.072 mmol) in CH 2 Cl 2 (10 mL), and the yellow solution was stirred for 2 h. The solvent was removed under vacuum at room temperature (to prevent the evolution of the complex), and Et 2 O (10 mL) was added. The resulting suspension was filtered, and the solid was washed with Et 2 O (2 × 5 mL) and air-dried to afford complex 6d as a colorless solid.  , 1 H, o-H, Ph). The 1 H resonance corresponding to the NH 2 group was not observed. 13  Synthesis of [Pd{C,N-CH(C 5 H 8 )CHC(Ph)C(CO 2 Me)-C 6 H 4 CH 2 CMe 2 NH 2 -2}Cl]·1/2CHCl 3 (7d·1/2CHCl 3 ). Method A. In a Carius tube, methyl phenylpropiolate (48 μL, 0.324 mmol) was added to a solution of palladacycle e (120 mg, 0.156 mmol) in CHCl 3 (10 mL), and the mixture was heated at 65°C for 2 h. The yellow solution was concentrated to ca. 1 mL, and Et 2 O was added (20 mL). The suspension was filtered, and the solid was washed with Et 2 O (2 × 5 mL) and air-dried to give complex 7d·1/2CHCl 3 as a pale yellow solid. Yield: 37 mg, 0.061 mmol, 20%. The filtrate was contentrated to ca. 2 mL, and n-pentane (20 mL) was added. The suspension was filtered, and the yellow solid was air-dried to give a ca. 1 Synthesis of 8f. In a Carius tube, KO t Bu (50 mg, 0.445 mmol) was added to a solution of complex 7f (120 mg, 0.228 mmol) in dry CH 3 CN, under an N 2 atmosphere (10 mL), and the mixture was heated at 78°C for 3 days. Decomposition to metallic palladium was observed. The solvent was removed, n-pentane (20 mL) was added, and the mixture was filtered through a plug of Celite. The solvent was removed from the filtrate, the residue was dissolved in Et 2 O (10 mL), and HOTf (0.01 mL, 0.113 mmol) was added. The resulting suspension was filtered, and the solid was washed with Et 2 O (2 × 2 mL) and air-dried to give compound 8f as a colorless solid. Yield  Synthesis of 9f. TlOTf (84 mg, 0.237 mmol) was added to a solution of complex 7f (125 mg, 0.237 mmol) in acetone (15 mL), and the mixture was stirred at room temperature for 12 h under an CO atmosphere, using a toy balloon. Decomposition to metallic palladium was observed. The suspension was filtered through a plug of Celite, the filtrate was concentrated to ca. 1 mL, and Et 2 O (20 mL) was added. The suspension was filtered, and the solid was washed with Et 2 O (2 × 2 mL) and air-dried to give the compound 9f as a colorless solid. Yield: 103 mg, 0.177 mmol, 75%. Mp: 223°C. Synthesis of 10c. In a Carius tube, TlOTf (72 mg, 0.204 mmol) was added to a suspension of the complex 7c·CHCl 3 (100 mg, 0.161 mmol) in acetone (15 mL) and the mixture was stirred for 15 min. CO was bubbled through the suspension for 3 min, the pressure of CO was increased to 1 atm, the tube was sealed, and the mixture was stirred at room temperature for 20 h. Decomposition to metallic palladium was observed. The suspension was filtered through a plug of Celite, the filtrate was concentrated to ca. 1 mL, and Et 2 O (20 mL) was added. The suspension was filtered, the solvent was removed from the filtrate, and the solid residue was stirred in n-pentane (20 mL). The resulting suspension was filtered, and the solid was washed with n-pentane (2 × 5 mL) and air-dried to give the compound 10c as a colorless solid. Yield: 84 mg, 0.152 mmol, 94%. Mp: 160°C. Λ M (Ω −1 mol −1 cm 2 ): 117.1 (c = 5.00 × 10 −4 M). Compound 10c was hygroscopic, and no satisfactory elemental analysis could be obtained. ESI-HRMS (m/z): exact mass calcd for C 27   Synthesis of 10d and 9d. In a Carius tube, TlOTf (50 mg, 0.141 mmol) was added to a solution of complex 7d·1/2CHCl 3 (75 mg, 0.124 mmol) in acetone (15 mL), and the mixture was stirred for 2 h. CO was bubbled through the suspension for 2 min, the pressure of CO was increased to 1 atm, the tube was sealed, and the mixture was stirred at room temperature for 15 h. Decomposition to metallic palladium was observed. The suspension was filtered through a plug of Celite, the solvent was removed from the filtrate, and Et 2 O (20 mL) was added. The mixture was filtered through a plug of Celite, the filtrate was concentrated to ca. 1 mL, and n-pentane (20 mL) was added. The resulting suspension was filtered, and the solid was washed with n-pentane (2 × 5 mL) and air-dried to give the compound 10d as a colorless solid. Yield: 60 mg, 0.100 mmol, 81%. Relevant crystallographic data, details of the refinements, and details (including symmetry operators) of hydrogen bonds for the compounds anti-1a, anti-1b, syn-1b, anti-2a·CH 2 Cl 2 , syn-2a, anti-2b· CHCl 3 , syn-2b, syn-3b·CH 2 Cl 2 , 6b·H 2 O, 7c·CHCl 3 , 7d·1/2CHCl 3 , 7f, 8f, 9d, 9f·Et 2 O, and 10c·H 2 O are given in the Supporting Information.